JP7597558B2 - Film-forming topical preparations - Google Patents

Description

The present invention relates to a film-forming topical preparation.

Film-forming topical preparations have been developed that incorporate a film-forming agent into them, forming a thin film on the skin after the topical preparation is applied to the skin. Film-forming topical preparations do not require a support such as a patch, and are therefore expected to improve the feel of use.

Patent Document 1 describes an aerosol composition that contains nitrocellulose as a film-forming agent and has excellent drying and peeling properties.

JP 2005-281167 A

The present inventors have investigated film-forming topical preparations containing nitrocellulose and found that they do not adhere sufficiently to the skin and that the film cracks. The object of the present invention is to provide a film-forming topical preparation that has excellent adhesion to the skin and is less likely to cause cracks in the film.

The inventors conducted extensive research to solve the above problems and found that a film-forming topical preparation containing an absorption enhancer, particularly a surfactant, has excellent adhesion to the skin and is less likely to cause cracks in the film. Furthermore, they found that such a film-forming topical preparation improves the skin permeability of the drug, and skin permeation continues for about one week. Based on these findings, the inventors have completed the present invention.

That is, the film-forming topical preparation of the present invention contains a drug, an organic solvent, nitrocellulose, and an absorption enhancer.

The film-forming topical preparation of the present invention has excellent adhesion to the skin when made into an aerosol formulation, and the film is less likely to crack. In addition, the film-forming topical preparation of the present invention has excellent skin permeability of the drug.

FIG. 2 is a perspective view of the sprayer with the lid closed. FIG. 2 is a perspective view of the sprayer with the lid open. FIG. 2 is a perspective view showing the positional relationship between the can and a lid serving as a cover. FIG. 1 is a perspective view showing a spray can with a lid attached as a cover to the can. FIG. 1 is a perspective view showing a spray can with a lid attached as a cover to the can. FIG. 2 is a front view and a plan view of the sprayer with the lid closed. 7 is a cross-sectional view taken along line AA in FIG. 6. FIG. 8 is an enlarged view of line BB in FIG. FIG. 2 is a left side view and a top view of the can. FIG. 2 is a front view and a plan view of the can. FIG. 2 is a left side view and a top view of the sprayer with a lid attached to the can as a cover. FIG. 4 is an enlarged cross-sectional view showing the change in state of the upper part of the spray.

The film-forming topical preparation of the present invention contains a drug, an organic solvent, nitrocellulose, and an absorption enhancer.

The drug is not particularly limited as long as it can be administered transdermally. Specific examples include steroidal anti-inflammatory drugs such as prednisolone, dexamethasone, hydrocortisone, fluocinolone acetonide, betamethasone valerate, betamethasone dipropionate, clobetasone butyrate, and prednisolone succinate; methyl salicylate, glycol salicylate, indomethacin, ketoprofen, diclofenac, ibuprofen, ibuprofen piconol, flurbiprofen, felbinac, ketorolac, loxoprofen, suprofen, pranoprofen, tiaprofen, flufenamic acid, and tenidap. nonsteroidal anti-inflammatory agents and their ester derivatives, such as aspirin, actarit, mizoribine, oxaprozin, mofezolac, etodolac, auranofin, indomethacin funercil, etc.; antiallergic agents, such as tranilast, azelastine, ketotifen, ibudilast, oxatomide, emedastine, epinastine, etc.; antihistamines, such as diphenhydramine, chlorpheniramine, promethazine, tripelennamine, etc.; central nervous system drugs, such as chlorpromazine, nitrazepam, diazepam, phenobarbital, reserpine, etc.; Hormones such as insulin, testosterone, norethisterone, methyltestosterone, progesterone, clobetasol propionate, deprodone propionate, estradiol, etc.; antihypertensives such as clonidine, reserpine, guanethidine, efonidipine, alprenolol, nifedipine, bisoprolol, etc.; cardiac stimulants such as digitoxin, digoxin, etc.; antiarrhythmics such as propranolol, procainamide, ajmaline, pindolol, tulobuterol, mexiletine, etc.; coronary vasodilators such as nitroglycerin, isosorbide dinitrate, papaverine, nifedipine, diltiazem, nicorandil, etc.; lidocaine, procaine, benzocaine, tetrakisodium benzoate, etc. analgesics such as morphine, aspirin, codeine, acetanilide, aminopyrine, acetaminophen, etc.; muscle relaxants such as tizanidine, eperisone, tolperisone, inaperisone, dantrolene, etc.; antifungal agents such as acetophenylamine, nitrofurazone, pentamycin, naphthiomate, miconazole, omoconazole, clotrimazole, neticonazole, efinaconazole, butenafine, etc.; antineoplastic agents such as 5-fluorouracil, busulfan, actinomycin, pleomycin, mitomycin, etc.; urinary incontinence agents such as terolidine, oxybutynin, etc.; antiepileptic drugs such as nitrazepam, meprobamate, etc.; chlorzoxazone, levodopa, amantadine, selegiline, laminidine, etc. Anti-Parkinson's agents such as noladine and ropinirole; antiemetics such as granisetron, azasetron, ondansetron, ramosetron, and palonosetron; drugs for treating frequent urination such as oxybutynin and imidafenacin; calcium antagonists such as nifedipine, nicardipine, and nilvadipine; narcotic analgesics such as fentanyl and morphine; antidizziness agents such as diphenidol and betahistine; cardiovascular drugs such as benzothiazepine; antitussives and expectorants such as ketotifen, tulobuterol, and tranilast; cerebral circulation improvers such as vinpocetine, nicergoline, nicorandil, clentiaceme maleate, fasudil, benidipine, and efonidipine; cerebrovascular dementia agents such as docosahexaenoic acid, vinconate, and nebracetam; donepezil Examples of the drug include Alzheimer's treatment drugs such as benzodiazepine, amylidine, memantine, rivastigmine, galantamine, etc.; polypeptide hormone drugs such as rootinizing hormone-releasing hormone and thyrotropin releasing hormone; immunomodulators such as polysaccharides, auranofin, lobenzarit, etc.; cholagogues such as ursodesoxycholic acid, etc.; diuretics such as hydroflumethiazide, etc.; diabetes drugs such as tolbutamide, etc.; gout treatment drugs such as colchicine, etc.; smoking cessation aids such as nicotine, etc.; central nervous system stimulants such as methylphenidate, etc.; antipsychotic drugs such as olanzapine, risperidone, asenapine, etc.; hair growth agents such as minoxidil, etc.; vitamins; prostaglandins; hypnotic sedatives; autonomic nerve agents; and peripheral vasodilators. The above drugs may be in the form of a free form or a pharma- ceutically acceptable salt. From the viewpoint of skin permeability, acidic drugs such as ketoprofen, diclofenac, felbinac, and loxoprofen are preferred, and diclofenac or a pharma- ceutically acceptable salt thereof is particularly preferred. The drug concentration can be 1% by mass to 30% by mass (based on the total mass of the film-forming topical preparation (however, in the case of an aerosol preparation, based on the total mass of the drug solution excluding the propellant); the same applies below).

The organic solvent serves as a medium for dissolving or dispersing the drug and other ingredients. Specific examples include methanol, ethanol, isopropanol, ethyl acetate, n-butyl acetate, acetone, ether, trichloroethane, benzyl alcohol, methyl isobutyl ketone, and methyl ethyl ketone. From the viewpoint of solubility, it is preferable that the organic solvent is at least one selected from ethanol and ethyl acetate. The concentration of the organic solvent can be 60% to 90% by mass.

Nitrocellulose functions as a film-forming agent. For example, industrial nitrocellulose (nitrocellulose) conforming to the JIS K6703-1995 standard moistened with a moistening agent such as isopropanol at 25% to 35% by mass (based on the total mass of the product) can be used as nitrocellulose. Specific examples include RS 1/32, RS 1/16, RS 1/8, RS 1/4, RS 1/2, RS 1, RS 2, RS 5, RS 7, RS 20, RS 60, RS 120, RS 500, SS 1/8, SS 1/4, SS 1/2, and SS20 (manufactured by KOREA CNC LTD.). The concentration of nitrocellulose can be 3% to 18% by mass.

The absorption enhancer enhances the adhesion of the film-forming topical preparation to the skin and suppresses the occurrence of cracks in the film. The absorption enhancer may be any compound that has been known to have an absorption enhancing effect in the skin. Examples of the absorption enhancer include surfactants and fatty acid esters (isopropyl palmitate, isopropyl myristate, ethyl oleate, etc.). Examples of the nonionic surfactant include polyoxyethylene alkyl ethers such as polyoxyethylene oleyl ether, polyoxyethylene lauryl ether, and polyoxyethylene stearyl ether; polyethylene glycol fatty acid esters such as polyethylene glycol monooleate; polyoxyethylene glycerin fatty acid esters such as polyoxyethylene glyceryl monostearate; polyoxyethylene sorbitol fatty acid esters such as polyoxyethylene sorbitol tetraoleate; and polyoxyethylene polyoxypropylene alkyl ethers such as polyoxyethylene polyoxypropylene cetyl ether. From the viewpoint of enhancing the adhesion of the topical preparation to the skin and suppressing the occurrence of cracks in the film, the absorption enhancer is preferably a surfactant, and particularly preferably a nonionic surfactant or an anionic surfactant. The concentration of the absorption enhancer can be 1% to 15% by mass.

The film-forming topical preparation preferably contains a pH adjuster. By containing a pH adjuster, the skin permeability of the drug is improved. Examples of pH adjusters include hydrochloric acid, citric acid, gluconic acid, succinic acid, acetic acid, tartaric acid, lactic acid, boric acid, maleic acid, phosphoric acid, sulfuric acid, adipic acid, malic acid, glucono-δ-lactone, monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, triisopropanolamine, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, sodium bicarbonate, sodium citrate, sodium acetate, sodium lactate, calcium lactate, and meglumine. From the viewpoint of improving the skin permeability of the drug, the pH adjuster is preferably lactic acid. The concentration of the pH adjuster can be 0.1% by mass to 10% by mass.

In addition to the above ingredients, the film-forming topical preparation may contain plasticizers, moisturizers, stabilizers, preservatives, cooling agents, fragrances, etc.

Plasticizers include higher alcohols such as oleyl alcohol, octyldodecanol, myristyl alcohol, isostearyl alcohol, and lauryl alcohol.

Humectants include polyhydric alcohols such as sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, liquid paraffin, 1,3-propanediol, and 1,4-butanediol.

Examples of stabilizers include oxybenzone, dibutylhydroxytoluene (BHT), sodium edetate, and UV absorbers (e.g., dibenzoylmethane derivatives).

Preservatives include paraoxybenzoic acid esters (e.g., methylparaben, ethylparaben, and propylparaben, etc.).

Examples of cooling agents include thymol, l-menthol, dl-menthol, l-isopulegol, and peppermint oil.

The film-forming topical preparation may be in the form of a lotion, liniment, gel, etc., or may be in the form of an aerosol preparation.

When the film-forming topical preparation is in the form of an aerosol preparation, an aerosol composition can be produced by filling an aerosol container with a medicinal solution containing the above-mentioned components, attaching a valve to the container, and filling the container with a propellant. Furthermore, an aerosol preparation can be produced by attaching a spray button to the container.

The propellant may be any known substance used in aerosol preparations, such as dimethyl ether, liquefied petroleum gas (LPG), nitrogen gas, carbon dioxide gas, or alternative fluorocarbon gas. The ratio (mass ratio) of the drug solution to the propellant may be 1:9 to 9:1.

The container for holding the aerosol composition may be a container commonly used for aerosol formulations. Typically, a metal container made of aluminum, steel, tinplate, or the like is used, and the inner surface of the metal container may be coated with an epoxy resin, a phenolic resin, a polyamideimide resin, or the like.

The structure of spray 1, which is an example of a container for storing an aerosol composition, will be described with reference to Figures 1 to 12. Spray 1 is a device that uses a high-pressure propellant to spray a given substance (e.g., a film-forming topical preparation) in the form of mist, foam, etc.

1 and 2 are both perspective views of the spray 1. The spray 1 includes a can 10 that contains an aerosol composition and a lid 20 that is removably attached to one end of the can 10. FIG. 1 shows the lid 20 in a closed state, and FIG. 2 shows the lid 20 in an open state. In this disclosure, the side on which the lid 20 is closed is defined as the upper side of the spray 1, and the opposite side, i.e., the bottom side of the can 10, is defined as the lower side of the spray 1. An injection button 11 is provided at the upper end of the can 10. An injection hole 12 is provided on the side of the injection button 11. When a user presses the injection button 11 toward the bottom of the can 10, the aerosol composition is released from the injection hole 12 to the outside. A side wall 13 is provided to surround at least a part of the side of the injection button 11. A receiving frame 14 formed in a concave shape (e.g., U-shaped) facing downward is provided on the part of the side wall 13 facing the injection hole 12. A cylindrical protrusion extending upward is formed in the center of the end face (top surface) of the lid 20. A through hole 21 is formed inside the protrusion along the vertical direction (also called the axial direction of the lid 20). A groove 22 is formed around the entire circumference of the outer surface of the protrusion. In other words, the groove 22 is formed along the through hole 21.

3 is a perspective view showing the positional relationship between the can 10 and the lid 20 when the lid 20 is attached to the can 10 as a cover. Figures 4 and 5 are perspective views showing the spray 1 with the lid 20 attached to the can 10 as a cover. Figure 4 is a view of the spray 1 from the injection hole 12 side, and Figure 5 is a view of the spray 1 from the opposite side. As shown in these figures, the receiving frame 14 of the can 10 and the groove 22 of the lid 20 are formed so that the groove 22 fits detachably into the receiving frame 14. The user can attach the lid 20 to the can 10 by placing the lid 20 sideways against the can 10 and pushing the lid 20 into the can 10 so that the groove 22 fits into the receiving frame 14. As a result, the can 10 and the lid 20 are integrated so that the injection hole 12 and the internal space 23 of the lid 20 are in communication. "The injection hole and the internal space of the lid are in communication" means that the injection hole and the internal space are connected so that the aerosol composition discharged from the injection hole can pass through the internal space of the lid. The spray range of the aerosol composition is limited by the internal space 23. That is, the lid 20 attached in front of the injection hole 12 (i.e., in the direction of injection of the aerosol composition) functions as a cylindrical cover to limit the spray range. The mark 11a formed on the end face (top face) of the injection button 11 indicates the direction in which the injection hole 12 is located, and also indicates the side to which the lid 20 is attached as a cover.

Figure 6 shows a front view and a plan view of the sprayer 1 with the lid 20 closed. In this disclosure, the side directly facing the injection hole 12 is defined as the front of the sprayer 1. The left side view, right side view, and back view of the sprayer 1 are the same as the front view. The bottom view of the sprayer 1 is represented by a single circle. As shown in the plan view, the injection button 11 is visible through the through hole 21 of the lid 20 even when it is closed.

Figure 7 is a cross-sectional view taken along line A-A in Figure 6. Figure 8 is an enlarged view taken along line B-B in Figure 7. The internal space 15 of the can 10 that contains the aerosol composition is connected to the injection hole 12 by a thin tubular passage 16 that extends vertically. In response to pressing the injection button 11, the aerosol composition passes from the internal space 15 through the passage 16 to the injection hole 12, and is sprayed out from the injection hole 12.

Figure 9 shows a left side view and a top view of can 10. The right side view of can 10 is symmetrical to the left side view. Figure 10 shows a front view and a top view of can 10.

Figure 11 shows a left side view and a plan view of the sprayer 1 with the lid 20 attached to the can 10 as a cover. The right side view of the sprayer 1 is symmetrical to the left side view. Figure 12 is an enlarged cross-sectional view showing the state change of the upper part of the sprayer 1. The diagram showing state S1 is a cross-sectional view taken along line D-D of Figure 11, enlarged based on line C-C of the same figure. State S1 is the initial state in which the spray button 11 is not pressed. When the user presses the spray button 11, the upper part of the sprayer 1 transitions to state S2. In state S2, the spray hole 12 and the central axis 100 of the lid 20 (and the internal space 23) coincide or nearly coincide. When the user stops pressing the spray button 11, the upper part of the sprayer 1 returns to state S1.

As described above, a spray according to one aspect of the present disclosure includes a can having a spray button with a spray hole and a side wall surrounding at least a portion of the side of the spray button, and a lid that is removably attached to the can. A through hole corresponding to the spray hole and a groove along the through hole are formed in the end of the lid. A concave receiving frame is formed in the portion of the side wall facing the spray hole. The groove fits removably into the receiving frame, thereby connecting the spray hole and the internal space of the lid.

Test Example 1: Evaluation of Water Resistance The components shown in Tables 1 and 2 were weighed out (unit: parts by weight) and mixed until uniform to obtain topical preparations. The solubility of the obtained topical preparations, the presence or absence of film formation, and the water resistance of the film were evaluated under the following conditions.

Solubility Evaluation The solubility of the topical preparation was evaluated by visual observation.
Evaluation criteria: A: Uniformly dissolved; B: Separation into two layers occurs; C: Undissolved matter or precipitate occurs.

Evaluation of the Presence or Absence of Film Formation 0.1 g of the topical preparation was dropped onto a liner (plastic film) and then spread over an area with a diameter of 5 cm. The presence or absence of film formation was evaluated visually.
Evaluation criteria: A: A film is formed. C: A film is formed but not uniformly, or no film is formed.

Evaluation of water resistance of the film 0.1 g of the topical preparation was dropped onto a liner (plastic film), and then spread over an area of 5 cm in diameter to form a film. After the film was formed, purified water was dropped onto the film, and the state of the film was visually evaluated 5 minutes later.
Evaluation criteria: A: The coating is not dissolved and is attached. B: Part of the coating is dissolved or peeled off. C: The coating is dissolved.

As shown in Tables 1 and 2, topical preparations containing aminoalkyl methacrylate copolymer and nitrocellulose were confirmed to have excellent solubility, film-forming ability, and film water resistance. Taking water resistance into consideration, it was confirmed that nitrocellulose was the most excellent film-forming agent.

Test Example 2: Evaluation of skin permeation durability and improvement of cracking The components shown in Tables 3 and 4 below were weighed out (unit: parts by weight) and mixed until uniform to obtain a film-forming topical preparation. The skin permeation of the obtained topical preparation was evaluated under the following conditions.

Hairless Mouse Skin Permeability Test The amount of diclofenac permeated through the skin was measured using hairless mice for the prepared film-forming topical preparations. First, the dermis side of the excised hairless mouse skin was placed on a flow-through diffusion cell as the receptor liquid side. Then, 40 mg of each prepared film-forming topical preparation was dropped onto the hairless mouse skin (stratum corneum side) and spread to an area of 5 ^cm2 . Next, the cell was filled with phosphate buffered saline, and warm water was circulated around the cell periphery so that the skin surface temperature was 32±1°C. Sampling was performed every 6 hours, and the flow rate of the receptor solution obtained at each point was accurately measured, and the drug concentration was measured by high performance liquid chromatography, and the amount of skin permeation was measured from the measured values of flow rate and drug concentration.

Film adhesion and cracking evaluation Some of the topical preparations shown in Table 5 were filled into an aerosol container, and a valve was attached to the aerosol container, and then the mass ratio of the topical preparation to the propellant (dimethyl ether) was 1:1 to obtain a film-forming aerosol composition. Next, a spray button was attached to the aerosol container to produce a film-forming aerosol preparation. The obtained film-forming aerosol preparation was sprayed on the skin for 1 second, and the film properties after 4 hours were visually observed, and adhesion and cracking were evaluated according to the following criteria.
A: 90% or more of the adhesive is attached, and no cracks are observed. B: 90% or more of the adhesive is attached, but some cracks are observed. C: Less than 90% of the adhesive is attached, or many cracks are observed.

Topical preparations 12 and 13 were confirmed to have low skin permeability. Furthermore, topical preparation 14 had better permeability than topical preparations 12 and 13, but when made into an aerosol preparation, it was confirmed that adhesion to the membrane was reduced and cracks occurred (aerosol preparation 3).

On the other hand, topical preparations 15 and 16, which contain a surfactant as an absorption enhancer, were confirmed to have good skin permeability, and when made into an aerosol preparation, they also had excellent adhesion to the film and were able to suppress the occurrence of cracks (aerosol preparations 4 and 5). In addition, the results for topical preparations 17 to 19 confirmed that the addition of lactic acid as a pH adjuster further improved permeability.

Test Example 3: Confirmation of skin permeation durability in human skin The components shown in Table 6 below were weighed out (unit: parts by weight) and mixed until uniform to obtain a film-forming topical preparation. The human skin permeation of the obtained film-forming topical preparation was evaluated under the following conditions.

Human skin permeability test The amount of diclofenac permeated through the skin was measured using human skin cut (dermatome) to a thickness of about 500 μm from the stratum corneum side for testing the prepared film-forming topical preparation. First, the dermis side of the excised human skin was placed on the receptor liquid side and mounted in a flow-through diffusion cell. Then, 80 mg of the prepared film-forming topical preparation was dropped onto the human skin (stratum corneum side) and spread to an area of 5 ^cm2 . Next, the cell was filled with phosphate buffered saline, and warm water was circulated around the cell periphery so that the skin surface temperature was 32±1°C. Sampling was performed every 6 hours, and the flow rate of the receptor solution obtained at each point was accurately measured, and the drug concentration was measured by high performance liquid chromatography, and the amount of skin permeation was measured from the measured values of flow rate and drug concentration.

As is clear from the results shown in Table 7, it was confirmed that the obtained film-forming topical formulation maintained the skin permeability of the drug for one week.

1...spray, 10...can, 11...spray button, 11a...mark, 12...spray hole, 13...side wall, 14...receiving frame, 15...internal space, 16...passage, 20...lid, 21...through hole, 22...groove, 23...internal space.

Claims (6)

The composition contains a drug, an organic solvent, nitrocellulose , an absorption enhancer , and a pH adjuster .
The absorption enhancer is at least one selected from polyoxyethylene alkyl ethers and polyethylene glycol fatty acid esters.
Film-forming topical preparation. 2. The film-forming external preparation according to claim 1, wherein the absorption enhancer is at least one selected from the group consisting of polyoxyethylene oleyl ether and polyethylene glycol monooleate . 3. The film-forming external preparation according to claim 1, further comprising at least one plasticizer selected from the group consisting of oleyl alcohol, octyldodecanol, myristyl alcohol, isostearyl alcohol and lauryl alcohol. The film-forming external preparation according to any one of claims 1 to 3 , wherein the organic solvent is at least one selected from the group consisting of ethanol and ethyl acetate. The film-forming external preparation according to any one of claims 1 to 4 , wherein the drug is an acidic drug. The film-forming topical preparation according to any one of claims 1 to 5, which is an aerosol preparation.

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